Nicotine replacement therapy as an aid to quitting smoking has been practical for a large number of smokers ever since nicotine chewing gum (nicotine polacrilex) became available commercially. Nicotine gum is actually an ion-exchange resin that releases nicotine slowly when the patient chews, and the nicotine present in the mouth is delivered directly to the systemic circulation by buccal absorption. Nicotine gum, however, may be difficult to tolerate as a long-term treatment. The usefulness of nicotine gum formulations are limited because they taste bad, cannot be used effectively by denture wearers, and may lead to mouth ulcers and heartburn. Other difficulties associated with oral administration of nicotine include stomach upsets, nausea, rapid nicotine degradation, and irregular and unpredictable blood plasma levels. In addition, the success of nicotine gum in maintaining even irregular blood levels depends entirely on the patient following a prescribed chewing regime. This regime is extremely inconvenient, particularly for users who need fairly heavy doses.
Another means of nicotine replacement that is commerically available is transdermal administration of nicotine. For some time now, transdermal delivery of nicotine has been known to be a means of administering nicotine for smoking cessation therapy that could avoid the health hazards, adverse effects, and inconvenience of other means of nicotine administration, particularly nicotine gum. Delivery of drugs by the transdermal route has been known to be theoretically possible for many years. The earliest transdermal patches were medicated bandages, usually with the drug mixed into the adhesive, designed to bring a known quantity of drug to a known area of skin for a known time. Such devices do not control the rate at which the drug is released. Controlled release transdermal patches rely for their effect on delivery of a known flux of drug to the skin for a prolonged period of time, measured in hours, days, or weeks. Two mechanisms are typically used to control the drug flux from the patch: either the drug is contained within a drug reservoir, separated from the skin of the wearer by a synthetic membrane, through which the drug diffuses; or the drug is held dissolved or suspended in a polymer matrix, through which the drug diffuses to the skin. Patches incorporating a reservoir and membrane will deliver a steady drug flux across the membrane as long as excess undissolved drug remains in the reservoir; matrix or monolithic devices are typically characterized by a falling drug flux with time, as the matrix layers closer to the skin are depleted of drug. To date limited commercial exploitation of the transdermal administration route has been achieved, because of the many practical problems to be overcome with real systems. The skin is an effective barrier against the majority of drugs. Unless the delivery device is made unacceptably large, or the natural skin permeation rate of the drug is increased, then the drug flux across the skin is inadequate for useful therapy. Thus although in theory any drug might be delivered by this route, serious investigation of candidate drugs has been limited to a few where there are strong indications for transdermal use, namely: small molecular size; short half-life, rapid metabolism by the liver; rapid degradation in the GI tract; other problems with oral administration; high in vivo skin permeability; and high potency, i.e. small effective therapeutic dose. Despite active work in the field since at least 1970, at present commercial patches are available for transdermal delivery of only seven drugs: nitroglycerin, isosorbide dinitrate, scopolamine, clonidine, estradiol, fentanyl, and nicotine.
The concept of applying the teachings of transdermal drug therapy to the delivery of nicotine has been described in the literature, and particularly in U.S. Pat. No. 4,839,174 and U.S. Pat. No. 4,943,435, herein incorporated by reference. Nicotine is a suitable candidate for transdermal therapy because it is volatile, highly lipid soluble, and permeates the skin easily. It is, however, a reactive liquid and a strong solvent. Therefore, transdermal nicotine systems must be made of materials that are compatible with nicotine and can release nicotine at a safe, useful flux.
In addition, these systems should be designed to exploit the benefits of controlled release transdermal therapy. In general, one of the recognized advantages of transdermal therapy as opposed to other drug administration techniques is the simplicity of the dosing regime. A patient using a transdermal patch is less likely to encounter compliance problems than one who is required to subject himself to percutaneous infusion or injection, to swallow pills, or to chew gum two or three times a day, for example. Also, a transdermal patch that has to be changed regularly once a day or once a week, for example, is preferred over one that has to be replaced several times a day, twice a week, or on an irregular schedule. Another major advantage of continuous transdermal delivery is that the blood plasma levels of the delivered agent remain relatively steady. In this way, the periodic fluctuations between plasma levels above the safe threshold and below the efficacy threshold that are often seen with oral tablets or injections are eliminated, as are the "highs" associated with addictive substances. Yet another advantage of a transdermal nicotine system relates to the clinical properties of nicotine, specifically skin irritation and toxicity. Nicotine is a known skin irritant, and a patch that exposes the skin to raw nicotine for any length of time is unacceptable. More importantly, nicotine is a very toxic substance. The lethal unit dose for an average adult is about 60 mg; one cigarette delivers about 1 mg of nicotine. Therefore, a patch that is to be effective for 12 or 24 hours may contain 30 to 60 mg of nicotine, which is a potentially lethal dose. A patient may be exposed to such a lethal dose if the patch is tampered with or ingested by a child, for example. Thus safety is a major concern, and a system that contains a high nicotine load must also be able to control release of that load in such a way that an individual using the patch on his skin is never exposed to a toxic dose. In addition, opportunities for accidental or deliberate misuse must be minimized if possible.
The primary use of transdermal nicotine systems to date has been for smoking cessation therapy. A study by Rose, J. E. et al., in Clin. Pharmacol. Ther. 1985, 38, 450-456, demonstrated that systemic delivery of nicotine in pharmacologically useful amounts was feasible by the transdermal route. Studies using human cadaver skin in vitro are likewise consistent with this finding. Typical permeabilities during the first day of patch use are on the order of 0.1 mg/cm.sup.2.h, increasing to 0.4 mg/cm.sup.2.h and more at later times. Systemic absorption of 20 mg of nicotine (approximately equivalent to smoking one pack of cigarettes) per day would then be theoretically achievable with a dermal administration area of about 10 cm.sup.2. This surface area is well within the range of appropriate sizes for transdermal delivery systems. In addition, human clinical studies by Dubois, J. P. et al. in Meth. and Find. Exp. Clin. Pharmacol. 1989, 11, 187-195, for example, have demonstrated that application of transdermal nicotine systems results in nicotine blood levels on the order of 10-20 ng/mL, which is comparable to the minimum nicotine blood levels of moderately heavy cigarette smokers. Application of patches for 16 to 24 hours resulted in relatively constant blood levels in this range, indicating that the systems are useful for reliable long-term delivery of nicotine.
Several groups of investigators have described clinical studies that investigated efficacy and safety of transdermal nicotine systems for smoking cessation. Abelin, T. et al. reported on the results of a double-blind study in The Lancet 1989, 1, 7-10. They determined that long-term use of a transdermal nicotine patch significantly increased the quit rate in cigarette smokers. The results of this study showed that the number of abstainers in the transdermal nicotine group after one, two, and three months of treatment was significantly greater compared to the placebo group. In another study reported by Mulligan, S. C. et al. in Clin. Pharmacol. Ther. 1990, 47, 331-337, the use of a transdermal nicotine patch in a 6-week placebo-controlled double-blind study resulted in a significant degree of smoking cessation. Finally, a report by Rose, J. E. et al. in Clin. Pharmacol. Ther. 1990, 47, 323-330 of a randomized double-blind trial indicates that certain smoking withdrawal symptoms were relieved by use of a transdermal nicotine system.
Of the many smoking withdrawal symptoms, however, craving for cigarettes is one of the most difficult to alleviate. As described in Steuer, J. D. and Wewers, M. E. in Oncology Nursing Forum 1989, 16, 193-198, cigarette craving is one of the most consistent, most severe, and earliest withdrawal symptoms experienced by those attempting to quit smoking. Some reports suggest that craving peaks over the first 24 to 72 hours of abstinence and then declines, although craving has been reported after five years of abstinence. Research is focusing on the factors that precipitate craving in an attempt to better understand and deal with the problem of relapse. Some investigators believe that certain smokers are much more likely than others to experience craving symptoms, especially when trying to quit smoking. Based on literature reports and his own investigations, Harrington (in Br. J. Soc. Clin. Psychol. 1978, 17, 363-371) reported that smokers can be separated by craving vs. noncraving status, and that these separate populations have different responses to smoking cessation therapy. (In his study, treatment consisted of various behavioral strategies, and nicotine replacement was not used). In particular, abstinence during treatment and success at the end of treatment were significantly related to being a noncraver.
With regard to nicotine replacement as a therapy for smoking cessation, some evidence indicates that low consistent blood levels of nicotine (as provided by transdermal nicotine, and to a lesser extent by nicotine gum) relieve some of the symptoms of nicotine withdrawal, but craving symptoms may not be among these (see Russell, M. A. H. in Nicotine Replacement: a Critical Evaluation; Pomerleau, O. F. and Pomerleau, C. S., Eds.; Alan R. Liss, Inc.: New York, 1988; pp 63-94). In contrast, cigarette smoking provides a initial sharp rise in blood level, which is missing in these nicotine replacement therapies. The blood level peak produced by cigarettes is both higher (between 30-40 ng/mL) and sharper (this peak is attained within 10 minutes) than the steadier levels obtained from gum or a transdermal system. Russell states that the optimal steady-state blood level for nicotine replacement is between 10-15 ng/mL, but that quick-rise effects are probably necessary for more complete relief from craving in the early stages of cigarette withdrawal. His investigations have indicated that a rise in nicotine blood level of at least 10 ng/mL in 10 minutes is required to obtain postsynaptic effects at nicotinic cholinergic receptors in the CNS and at autonomic ganglia. These postsynaptic effects may be responsible for drug-like "high" feelings such as light-headedness or dizziness experienced by cigarette smokers.
No other commercially available products for nicotine replacement in smoking cessation therapy have specifically addressed the issue of satisfying craving for nicotine. Instead, as mentioned above, they have generally been targeted towards providing a stable baseline level of nicotine in the blood. As described above, nicotine gum is one of the commercially available sources of nicotine for replacement therapy, and indeed is currently the most popular. Nevertheless, Russell (in Nicotine Replacement: a Critical Evaluation; Pomerleau, O. F. and Pomerleau, C. S., Eds.; Alan R. Liss, Inc.: New York, 1988; pg. 68) has stated that, compared with cigarette smoking, nicotine gum is a slow and inefficient source of nicotine. Nicotine gum cannot mimic the rapid peaks in the nicotine concentrations of mixed venous blood, or the transient high-nicotine post-inhalation boli in arterial blood, that are characteristic of cigarette smoking. In addition, during ad libitum clinical or experimental use, the 2-mg gum produces steady-state blood nicotine levels that average around one third of the blood level peaks obtained from cigarette smoking. Transdermal nicotine systems can be designed to provide higher steady-state blood levels of nicotine, but are similarly unable to provide blood level peaks or to provide a rapid increase in blood level. Thus both nicotine gum and transdermal nicotine compete with each in other as products providing steady-state nicotine blood levels, but do not satisfy craving symptoms for cigarettes in some smokers.
Other nicotine replacement products that are on the market or have been proposed in the literature have not been of serious interest in smoking cessation therapy, because of problems related to their use, and also because of limited ability to satisfy craving for cigarettes. Nicotine vapor has been delivered to patients in aerosol form, similar to the inhaler technology used to supply bronchial asthma medications, and in a "smokeless cigarette" such as that marketed by Advanced Tobacco Products under the trade name Favor.RTM.. Some data indicate, however, that these modes of nicotine delivery do not result in significant nicotine blood levels in patients after use. In addition, inhalation of these nicotine vapor products may be too irritating to the mucosa to be tolerable by patients. Another smokeless version of nicotine delivered to the buccal mucosa is provided by chewing tobacco, oral snuff, or tobacco sachets. Tobacco sachets, which are especially popular in Scandinavia and the U.S., contain ground tobacco in packets that are sucked or held in the mouth. However, as shown in FIG. 1 (from Russell, M. A. H., Jarvis, M. J., et al. Lancet 1985, 2, 1370), use of tobacco sachets results in nicotine blood levels that are more comparable to those resulting from nicotine gum use than from those resulting from cigarette smoking; i.e. they require approximately 30 minutes of use to attain the maximum level of approximately 12 ng/mL, which is less than half of the peak value from smoking one cigarette. One possible reason that nicotine from tobacco sachets is absorbed so slowly is that nicotine is released slowly into the mouth, as with nicotine gum; another may be that a significant proportion of the nicotine is swallowed, and therefore subject to the first pass effect of the stomach and liver. In any case, these oral delivery forms may be useful for producing low, steady-state nicotine blood levels, but they do not provide the peak levels needed to satisfy craving.
One U.S. patent describes a combination of two of these modes of nicotine delivery for smoking cessation therapy. U.S. Pat. No. 4,920,989 describes the use of transdermal nicotine systems to provide steady release of nicotine to the patient, combined with the use of a nicotine-containing aerosol spray for oral delivery. The aerosol spray is used periodically in order to provide the patient with sensations in the respiratory tract, and periodic peak blood levels of nicotine, similar to those obtained from cigarette smoke. As mentioned above, however, some reports in the literature suggest that delivery of nicotine by vapor inhalation does not result in significant nicotine blood levels in patients after use, and that inhalation of these nicotine vapor products may be too irritating to the mucosa to be tolerable by patients. In addition, inhaler devices for delivery of aerosol drug products are a much more cumbersome and less discrete dosage form than tablets or skin patches, and some patients are therefore reluctant to use them due to inconvenience and embarrassment. Finally, it is questionable whether this combination mode of therapy would satisfy cravings for cigarettes, because of the lack of proof that inhaled nicotine vapor is useful in providing peak blood levels of nicotine.
The present invention discloses the use of transdermal nicotine systems to provide steady release of nicotine to the patient, plus the period use of nicotine lozenges to provide rapid delivery of nicotine to the buccal mucosa, resulting in transient blood level peaks that mimic the effects of cigarette smoking. The literature describes other capsules, tablets and lozenges for oral delivery of nicotine, but these are designed to be the sole form of nicotine replacement for a patient trying to quit smoking. For example, WO 8803803 discloses a chewable capsule filled with a liquid containing 0.1-10.0 mg of nicotine, together with additives for improving flavor and dispersion. The capsules are provided in a variety of pH values to allow the patient a choice of nicotine absorption rate, and are especially intended as an aid to quitting smoking. Another nicotine capsule formulation is disclosed by M. E. Jarvik et al. (in Clin. Pharm. Ther. 1970, 11, 574-576) for ingestion as a smoking cessation aid. These capsules, however, were apparently swallowed whole by the subjects, according to the theory that intestinal absorption of nicotine could produce significant blood levels, intestinal absorption should be very low due to the intense first pass effect by oral route and consequent metabolism of nicotine in the GI tract. The study showed a small but significant decrease in the number of cigarettes smoked by subjects, but no quantitative measurements of nicotine blood levels were obtained.
The literature also describes different designs of tablets for delivering nicotine to the mouth and digestive system. BE 899037 discloses a tablet containing 0.1 to 5 mg nicotine as a base or water-soluble acid salt as an aid for quitting smoking. The tablet is intended to be sucked in the mouth so as to provide very low doses of nicotine to the patient. Wesnes and Warburton (in Psychopharmacology 1984, 82, 147-150; and Psychopharmacology 1986, 89, 55-59) discuss the use of nicotine tablets in experiments examining the effects of nicotine on learning and information processing. In the first experiment nicotine was added to dextrose tablets with a drop of tabasco sauce added to disguise the taste of nicotine. In the second experiment nicotine was added to magnesium hydroxide tablets, under the theory that an alkaline environment in the mouth would enhance buccal absorption. Again, tabasco sauce was added to the tablets to mask the taste of nicotine in both active and placebo tablets. The subjects were instructed to hold the tablets for 5 minutes in the mouth before swallowing, in order to maximize contact with the buccal mucosa.
Shaw (for example in GB 2142822 and U.S. Pat. No. 4,806,356) describes a nicotine lozenge prepared from a mixture of inert filler material, a binder, and either pure nicotine or a nicotine-containing substance by cold compression. The lozenges are intended to be held in the mouth as the dissolve slowly and release nicotine gradually in the buccal cavity, as a nicotine replacement for satisfying a craving for nicotine. It will be noted, however, that if the nicotine is intended to be released slowly into the mouth, then the corresponding blood level of nicotine is likely to rise slowly, instead of peaking rapidly as with cigarette smoking.
The present invention describes the use of transdermal nicotine systems to provide steady release of nicotine to the patient, resulting in consistent low nicotine blood levels. It also describes the periodic use of nicotine lozenges in conjunction with the transdermal therapy. The nicotine lozenges are designed to be held in the patient's mouth and sucked, and to rapidly release nicotine into the buccal cavity, resulting in transient blood level peaks that mimic the effects of cigarete smoking. Thus the patient is provided with a consistent transdermal dose of nicotine, plus transient oral doses that aid in satisfying cravings for cigarettes. This method of therapy more closely mimics the nicotine blood levels achieved by consistent smoking, and will provide greater protection against relapse than other nicotine replacement therapies for people who are trying to quit smoking.